20.500.12556/RUL-135985 Cystatin C deficiency increases LPS-induced sepsis and NLRP3 inflammasome activation in mice Cystatin C is a potent cysteine protease inhibitor that plays an important role in various biological processes including cancer, cardiovascular diseases and neurodegenerative diseases. However, the role of CstC in inflammation is still unclear. In this study we demonstrated that cystatin C-deficient mice were significantly more sensitive to the lethal LPS-induced sepsis. We further showed increased caspase-11 gene expression and enhanced processing of pro-inflammatory cytokines IL-1β and IL-18 in CstC KO bone marrow-derived macrophages (BMDM) upon LPS and ATP stimulation. Pre-treatment of BMDMs with the cysteine cathepsin inhibitor E-64d did not reverse the effect of CstC deficiency on IL-1β processing and secretion, suggesting that the increased cysteine cathepsin activity determined in CstC KO BMDMs is not essential for NLRP3 inflammasome activation. The CstC deficiency had no effect on (mitochondrial) reactive oxygen species (ROS) generation, the MAPK signaling pathway or the secretion of anti-inflammatory cytokine IL-10. However, CstC-deficient BMDMs showed dysfunctional autophagy, as autophagy induction via mTOR and AMPK signaling pathways was suppressed and accumulation of SQSTM1/p62 indicated a reduced autophagic flux. Collectively, our study demonstrates that the excessive inflammatory response to the LPS-induced sepsis in CstC KO mice is dependent on increased caspase-11 expression and impaired autophagy, but is not associated with increased cysteine cathepsin activity. cystatin C lipopolysaccharide NLRP3 inflammasome autophagy cysteine proteases interleukin-1 (IL-1) cistatin C lipopolisaharid vnetni virus NLRP3 true false true Angleški jezik Slovenski jezik Članek v reviji 2022-04-05 14:29:03 2022-04-05 14:29:07 2022-09-15 04:13:05 0000-00-00 00:00:00 2021 0 0 18 str. iss. 8, art. 2071 Vol. 10 2021 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616-092 2073-4409 10.3390/cells10082071 72910851 RAZ_Biasizzo_Monika_2021.pdf RAZ_Biasizzo_Monika_2021.pdf 1 AE827EE89066A5F4D71D45F1653A4C69 d17d89d32d07dd473da98c278fb88594ca94d899111dce7e83eba1f80ed190c6 3546c47f-b4dc-11ec-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=155354 https://www.mdpi.com/2073-4409/10/8/2071 1 f4c38174-b4db-11ec-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=155353 Medicinska fakulteta Fakulteta za kemijo in kemijsko tehnologijo 0 0 0